Epidemiological, preclinical and clinical data suggests that inflammation plays a key role in colon-rectal cancer (CRC). Studies suggest that CRC risk is high in subjects with ulcerative colitis (UC) and Crohn disease (CD). Globally, CRC is the third most commonly diagnosed cancer and second leading cause of deaths in United States. It is estimated that there will be 1.35 million new cases and about 700,000 deaths worldwide at annual bases; and 142,820 new cases diagnosed in the United States in 2013 and 50,830 deaths due to this disease. It is widely reported and accepted that inflammatory genes, such as cyclooxygenase-2 (COX-2) expression, and its metabolite prostaglandin-E2 (PGE2) play key roles in CRC progression and metastasis. There are multiple levels of control exits for regulation of PGE2 production. Use of anti-inflammatory agents displayed protective effects in CRC, which stimulated interest in primary prevention with use of agents belonging to nonsteroidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors. Compelling protective effects were shown by NSAIDs like aspirin and selective COX-2 inhibitors in animal models and clinical research. Though NSAIDs were effective in showing preventive effects of CRC, they are associated with gastrointestinal bleeding due to inhibition of cyclooxygenase-1 (COX-1) along with cyclooxygenase-2 (COX-2). A large number of clinical studies with varying designs followed with similar results with NSAIDs and selective COX-2 inhibitors. Selective COX-2 inhibitors provided better efficacy and to a certain extent were devoid of gastrointestinal toxicities. There have been several placebo-controlled trials on the use of COX-2 inhibitors in the prevention of adenoma recurrence in Familial Adenomatous polyposis (FAP), an inherited disorder characterized by colon and rectal cancer, and sporadic patients with a prior history of adenoma. One of the trials with selective COX-2 inhibitor provided 30-55% lower risk of adenoma recurrence it was associated with higher risk of cardiovascular (CV) events. Therefore, the cancer-protective benefits of selective COX-2 inhibitors appear to be outweighed by an increase in risk of cardiovascular events, due to platelet dependent thrombosis. The reason for this toxicity appears to be due to imbalance of COX and lipoxygenase (LOX) enzymes due to inhibition of COX-2 leading blocking PGE2 but also prostaglandin-E2 (PGI2); moreover, shifting metabolism LOX metabolites such leukotrienes (LTs). Both low levels of PGI2 and high levels of LTs are established risk factors of thrombosis and CV risk.
5-LOX and its downstream molecule leukotriene B4 (LTB4) are identified to be involved in CRC development. Similar to COX-2 and its downstream PGE2, 5-LOX and LTB4 are highly elevated in CRC, related to tumor size and invasion. Thus, blocking of PGE2 and LTs by sparing the PGI2 is a significant issue in developing anticancer agents without unwanted side effects and CV risk. Mechanistically, one such control is via expression of specific prostaglandin E synthases, which utilize the COX product prostaglandin-H2 PGH2 to produce PGE2. Microsomal prostaglandin E synthase-1 (mPGES-1) is, like COX-2, induced by pro-inflammatory stimuli and up-regulated in colorectal tumors and major contributor of PGE2. In support of this hypothesis, loss of mPGES-1 expression is reported to suppress intestinal neoplasia in Apc-mutant mice. Thus, selectively targeting mPGES-1 would block the production of PGE2 but spare the PGI2 which is required for the anti-thrombotic effects in avoiding cardiovascular (CV) risk. COX-1 and COX-2 are responsible for production of PG's, thus inhibiting can reduce pain and inflammation, however, this inhibition can also cause alternative processing of arachidonic acid via 5-LOX pathway resulting in an increase of proinflammatory and gastrotoxic LT's.
Molecular mechanistic studies suggest that targeting mPGES-1 and 5-LOX would spare the PGI2 and cardiovascular and renal side effects. Licofelone (2,2-dimethyl-6-(4-chloropheny-7-phenyl-2,3-dihydro-1H-pyrrazoline-5-yl] acetic acid), discovered by Merckle GmbH and developed by EuroAlliance, is a competitive 5-LOX, COX-1 and COX-3 inhibitor. It decreases the production of both LTs and PGs, thereby reducing inflammation and pain with low gastrotoxicity. It thus possesses significant analgesic, anti-inflammatory, and antiasthmatic effects at doses that cause no gastrointestinal (GI) side effects. Thus, designing and development of anti-inflammatory drugs which are devoid of GI toxicity, and prothrombotic and nephro-toxicities are a significant clinical need for many diseases including CRC prevention and treatment.